June 19, 2010

Questioning the basic rules of science is responsible for some of the more fantastic cures in medical history. Performing organ transplantation across blood groups will probably fit into this category.

Three months ago, Rajan Ravichandran, Director, MIOT Institute of Nephrology, and his team, pulled off such a feat as they used a kidney from a donor with ‘B' blood group on a recipient with ‘O' blood group. Normally, that would have killed the patient on the operating table. Not this time though. Using a special procedure called Double Filtration Plasmapheresis (DFPP) evolved by the Japanese, the team had the patient, S, discharged in a week, and back at his software job in three months' time.

Dr. Ravichandran says: “The most essential requirement in transplantation is a blood group match. Ideally, the patient's own blood group, or, in the event it is not available, any group for which his blood does not carry antibodies.” Antibodies are used to detect and neutralise foreign bodies, being the base for both allergy and immunity in the human body.

While ‘O' is a universal donor, it has antibodies to ‘A' and ‘B' groups; similarly, ‘A' has antibodies to ‘B'; and ‘B'group, antibodies to ‘A'. Only the ‘AB' group, a universal recipient, has no antibodies. The Rhesus factor (+ve, –ve) is irrelevant in the transplantation process. Tissue matching is also not done for most ‘cadaver transplants' and the availability of new generation immunosuppressant drugs has helped patients tide over that mismatch, Dr. Ravichandran clarifies.

If the right blood group is not chosen, the moment the recipient's blood begins to flow into the transplanted organ (which will continue to harbour micro red blood corpuscles from the differently matched donor's kidney), it will turn blue and will be rejected by the body. Patient S (with blood group ‘O') had a donor in his father, who was in ‘B' group. Thanks to the Japanese technology, the team removed the specific antibody (in this case, ‘B') in the patient's blood through the DFPP process over three sittings.

Meanwhile, titres to measure the presence of antibodies in the blood were done periodically. At the right time, the transplantation surgery was fixed. Post transplantation, the patient received special monoclonal antibody rejection injection to prevent new antibody formation. This process does not compromise the health of the patient in any way, Dr. Ravichandran adds.

In Japan, where the technology was evolved, over 450 successful cross-blood-group transplantations have been perfomed, he explains. The success at a 10-year survival rate is equal to that of any regular kidney transplantation. At the Mayo Clinic in the United States, over 40 such transplants have been performed using a different technique. Closer home, while several attempts at cross-blood-group transplantation have been made over the years (including by Dr. Ravichandran), success was noted only six months ago at Christian Medical College, Vellore.

This process can be used across various organ transplants, Dr. Ravichandran says, adding that it could also help people who have rejected a transplanted organ many years later because of antibody formation. With lakhs of people with end stage kidney disease in India, there are only 5,000 transplantations that occur in a year. While efforts are being made to increase the donor pool, strategies such as DFPP would increase the chances of saving lives, Dr. Ravichandran states.

P.V.A. Mohandas, managing director, MIOT Hospitals, stresses on the need to communicate the tremendous possibilities of such procedures to the public. With a high burden of diabetes and hypertension in the population and the consequent impact in the number of people with kidney disease, efforts must be taken to make transplantation available to more people, he adds.

ALBANY -- A proposal to flip New York's organ-donation system on its head by presuming people are donors unless they indicate otherwise has the state Legislature buzzing.

Polls have found that the majority of New Yorkers would like to be donors, yet just 13 percent of residents 18 and older are on the state Donate Life Registry. More than 9,600 people in the state need organ transplants, according to the New York Organ Donor Network. Last year, there were just 423 deceased organ donors in New York.

"What we have in New York is a completely failed system," said Assemblyman Richard Brodsky, D-Greenburgh, whose daughter is a two-time kidney transplant recipient and who proposed the legislation.

"People are dying in New York this week because we have failed to create a system that maximizes the opportunities to keep them alive," Brodsky said.

Brodsky said his bills to implement "presumed consent" and prohibit family members from overriding donors' wishes have sparked a lot of interest. People approach him about it everywhere he goes, and individuals and religious groups have raised legitimate concerns.

Because of that, he's not pushing the proposal this session, he said.

"What I've said to anybody, whether they like it or they don't like it, we can't sustain the current system," said Brodsky, whose daughter, Julianne "Willie," received her second transplant four years ago and has become an advocate for changing the system.

He is working on other reforms on organ donations, such as requiring the state Department of Motor Vehicles to provide information on organ donations and creating an organ donation tax credit.

Brodsky, a candidate for state attorney general, co-sponsored legislation this session that would let people consent for giving an anatomical gift through an electronic signature. It passed both houses and goes to Gov. David Paterson for his consideration. Forty-five states allow electronic signatures for donor registries, the New York Organ Donor Network said.

Other states with low donor-registration rates are Texas (an estimated 2 percent), South Carolina (9 percent) and New Hampshire (10 percent), compared to 73 percent in Alaska, an April Donate Life America report found.

No states have "presumed consent" laws, although there have been attempts in several of them, including Maryland and Pennsylvania. Legislation is under consideration in Illinois. A bill was introduced in the Delaware Legislature two years ago.

A number of European nations, including France, Austria and Spain, have this kind of system in place, and they have seen an increase in organ availability, said Arthur Caplan, a bioethics professor at the University of Pennsylvania School of Medicine.

Polla have found that the majority of New Yorkers and Americans want to donate organs and tissues when they die, so the burden should be on the minority to opt out, Caplan said. A recent survey by the New York Alliance for Donation found 67 percent of state residents strongly support organ and tissue donation.

The use of the term "presumed consent" can make some people angry because they don't want presumptions made about what happens to their bodies after they die, Caplan said. He prefers to call it "default to donation."

To get traction in this country, "It's going to take one state to sort of jump out there and show that it works," said Caplan, who has been working on the issue since 1983.

Organ-donation groups report that common objections to presumed consent are a belief that physicians may not work as hard to save them and the government and health care systems would have too much power.

The Long Island Coalition for Life Inc. opposes Brodsky's legislation, which is sponsored in the Senate by Senate Health Committee Chairman Thomas Duane, D-Manhattan.

"This legislation opens up the door to abuse via hastened death of vulnerable people and overriding of family concerns," Jerome Higgins, chairman of the coalition, wrote in a memo to lawmakers. "It also goes a step further toward turning human organs into commodities. The sick and disabled need to be protected, not exploited for their body parts."

The Rev. Jason McGuire of New Yorkers for Constitutional Freedoms, an evangelical Christian group, said organ donation should be voluntary. There are personal-privacy and big-government issues involved. In general, evangelical Christians don't oppose organ donations, although they are not permitted in certain religions, he said.

It's "bizarre" to think presumed consent would go over well with ordinary Americans, said Mary Ann Baily, a fellow of the Hastings Center, a bioethics research group in Garrison, Putnam County, and a graduate faculty member at Sarah Lawrence College in Yonkers. They are frustrated with taxes, and the idea that government would have control over their organs likely is even less popular with them.

"The problem is it's quite easy not to even notice that box that says, 'I don't want to donate my organs,"' she said, referring to a driver's license form. "You should only presume consent when it really is clear that everybody would consent if they thought about it."

One of the major reasons for not having enough organs is people have to die in a certain way and in a hospital for their organs to be viable for use by others. Most families will give consent if they are asked in the right way, said Baily, who once sat on an Institute of Medicine committee that looked at how to boost organ donations.

But even if all available organs were taken, it wouldn't eliminate waiting lists, Baily said. Hospitals may not get the maximum number of organs possible if they and organ banks aren't well organized, she said.

"This law, it seems to me ... is going to stir everybody up and probably not increase organ donations," she said.

Physicians who conduct transplants "don't hope for somebody to die to be a donor," said Dr. Luca Cicalese, chairman and director of the Texas Transplant Center and surgery professor at the University of Texas Medical Branch.

"The reality of the system is that we don't have anything to do with donors," he said.

Transplant staff don't talk to the family of someone who is dying, Cicalese said. That's done by organ-bank staff members, he said.

"There is a system that is very careful in keeping things separate and avoiding conflicts of interest," he said.

Under presumed consent, the family would still be asked whether they wanted the relative's organs to be donated, Cicalese said.

"I think the education is very important. Many people don't understand that one donor can actually save many, many people's lives," he said.

WASHINGTON - At the request of Congressman Anh "Joseph" Cao (LA-02), the House Committee on Oversight and Government Reform held a hearing today on "Viral Hepatitis: the Secret Epidemic."

Public health records show viral hepatitis, which is transmitted mainly through contact with infected blood, is the most common blood borne infection in the United States, and it is the nation's leading cause of liver cancer and liver transplants, representing one of the largest and costliest disease burdens. Over the next decade, about 150,000 Americans will die from liver cancer and end-stage liver disease associated with chronic hepatitis B and C.

In prepared remarks submitted for the record, Cao pointed out that between 3.5 to 5.3 million Americans--about 1% to 2% of the population--are infected with viral hepatitis. In Louisiana, some 80,000 people--about 1.8 percent of the population--have hepatitis C. Approximately 20,000 people have hepatitis B and 4.6% of adults are considered at risk.

In New Orleans and Jefferson Parish, about half of hepatitis B patients are Asian Americans in contrast to only 5% of the overall population. Among African Americans, rates of hepatitis C are twice the national average.

Cao said, "This is a grave public health crisis and human tragedy, especially given the asymptomatic nature of the disease, as 65% to 75% of individuals living with viral hepatitis are unaware they are infected until they develop symptoms of liver disease and cancer years later." Cao pointed out that only about half of the cases of hepatitis C in Louisiana are detected for inclusion on the state's hepatitis register.

The committee considered, among other things, a recent Institute of Medicine (IOM) study that found the government has failed to raise awareness, dedicate appropriate resources and properly identify, screen, treat and prevent viral hepatitis.

For example, the administrative budget for the Division of Viral Hepatitis of the Centers for Disease Control and Prevention represents only 2% of the agency's entire budget. Despite projected costs of $16 billion a year nationally, the federal government gives states an average of only $90,000 a year for hepatitis prevention in adults. This provides for little more than one staff position's salary and does not fund any actual services.

The report concluded that the federal government's "current approach to the prevention and control of chronic hepatitis B and hepatitis C is not working." The IOM attributed the lack of knowledge and awareness among the American public and health providers, the large health disparities, and the high mortality rates to the lack of dedicated resources and national leadership.

Cao said, "By calling attention to viral hepatitis at the Congressional level, we hope to focus attention on this 'secret epidemic' and channel resources toward its prevention, more effective treatmen and cure."

A potentially groundbreaking study has shown that a nutritional supplement was effective in treating patients with hepatitis C who do not respond to standard antiviral therapy. The research, published in the June 7, 2010 issue of the World Journal of Gastroenterology, was conducted by doctors at the National Institute of Gastroenterology in Havana, Cuba.

Called Viusid, the supplement contains ascorbic acid (vitamin C), zinc, and glycyrrhizic acid (licorice). The antioxidant properties of these ingredients work by preventing the proliferation of free radicals, and their immunomodulatory effects help strengthen the immune system.

Patients with hepatitis C who did not respond to standard therapy received either 3 doses of Viusid daily or placebo. Certain chemicals in the body that gauge levels of oxidative stress and immune response were measured. Patients on Viusid showed significant improvement in these parameters when compared to the control group.

Unfortunately, only 50% of people with hepatitis C respond to the single treatment currently available—the combination of the drugs peginterferon and ribavirin. Trials for other drugs had to be stopped due to serious side effects, the researchers explained in their paper.

“Hepatitis C virus infection is one of the most important causes of chronic liver disease,” stated the authors. “There is an obvious need for the continuous development of new treatment strategies.”

6/13/10 - Exalenz Bioscience Ltd. (TASE:EXEN) has successfully completed the feasibility study to test the effectiveness of its BreathID device to diagnose the severity of liver disease in people with Hepatitis B. The trial was carried out at the Prince of Wales University Hospital in Hong Kong.

The trial included 47 patients. The BreathID device was able to distinguish between patients in early stages of cirrhosis of the liver and patients with late-stage cirrhosis with an accuracy of 91 percent. Early diagnosis of cirrhosis is important, because it greatly improves treatment and the patients and medical teams' ability to deal with the disease.

The company intends to expand the study to 100 patients, in order to demonstrate the effectiveness of the BreathID device in predicting clinical results.

The BreathID system can assess a range of liver and gastrointestinal disorders by molecular analysis of patients' exhaled breath. It uses a laser-like light source to pinpoint real-time changes in carbon 13-carbon 12 isotope ratios at an accuracy level of single parts per million.

Exalenz cautioned that the test results are insufficient to know whether it can commercialize the BreathID device in the US, Asia, or anywhere else. Commercialization will be dependent on successful clinical trials and the obtaining of regulator permits.

When people think of the Fairfax County Government Center, they don’t normally picture people competing in a foot race. But for the past decade, it’s been the site of the Tim Harmon Memorial 5K Run/Walk.

Now, it’s again time for the 11th annual race honoring a former county employee and raising money toward a cure for Hepatitis C. It’s slated for Saturday, June 26 at 8:30 a.m., rain or shine, and signups are still open. Cost is $25, and registration is at www.racepacket.com, or in person on race day, from 7-8:15 a.m.

“It’s nice to do a race at the Government Center because parking is right there,” said race director Tom Cook of Chantilly's Armfield Farm community. “You can walk to the starting line.”

The course is mostly flat and fast, beginning and ending in front of the Government Center and going out to West Ox Road and Monument Drive. Participants may either walk or run. For more information, call 703-934-8756, e-mail peggy.cook@fairfaxcounty.gov or see http://www.timharmon5k.org/ .

Harmon died of Hepatitis C in 1999 at age 51. But before then, he did all he could to help people struggling with addiction. He worked 20 years for Fairfax County and was Director of Residential Services for Alcohol and Drug Services [ADS].

He also founded a substance-abuse treatment program for teens. Because of his efforts, seven new residential treatment programs were opened. He also helped expand those at A New Beginning and Fairfax Detox in Chantilly, New Generations in Vienna, plus Crossroads and Sunrise House.

"Tim hired me in 1984 as a substance-abuse counselor [for ADS]," said Cook, who still holds that position and works with teens. "He was a driving force behind many of this county’s services."

The race is run to remember Harmon and to raise awareness of hepatitis C. Proceeds go to charities including the Hepatitis Foundation, the American Liver Foundation and local drug-treatment centers, including Sunrise in Fair Oaks. Harmon left behind a wife and two daughters, now grown, plus a 10-year-old grandson he never saw. Matthew was born the year after he died; but each year, he participates in the race.

Prizes in the 5K are awarded to the top three, male and female overall finishers, plus the top three finishers in 14 age groups in five-year increments. The race has four divisions: runners/walkers, Fairfax County employees, baby joggers and public safety. Fire and police personnel will compete against each other for team and individual trophies.

Registered participants receive custom T-shirts designed by Kay Rankin. They’re white and adorned with a replica of a running shoe in the Hepatitis Foundation’s colors of yellow and red. “Kay does a great job, every year,” said Cook.

Sports Plus & Battlefield Screen, CASSADAY Inc., MicroPact Engineering, Olympus Auto Parts and Inova Comprehensive Addiction Treatment Services are the major sponsors. More than 100 trophies, plaques and medals will be presented, plus doorprizes from local restaurants and merchants.

Silent auction items include signed footballs by Brian Griese of the Tampa Bay Buccaneers and his father Bob Griese, the Hall of Fame quarterback from the Miami Dolphins; a hockey puck signed by Washington Capital Matt Bradley; and lots of Washington Redskins memorabilia, including a signed, autographed picture of Redskins greats Art Monk and Darrell Green being inducted into the Hall of Fame.

Bidders can also bid on a mini football helmet signed by Redskins linemen, the Hogs; photos of Redskins Jeff Bostic and Joe Jacoby; a full-size football helmet signed by Randy White (ex-Dallas Cowboy and University of Maryland lineman); and running batons signed by great American distance runners, Bill Rodgers and Joan Benoit-Samuelson.

Adding to the day’s fun is a live, classic-rock band, The Sock Monkeys, who'll entertain before, during and after the race. Post-race refreshments such as bagels, granola bars, juice and soda will be available, and Piedmont School of Massage will give free massages after the race to the runners.

"Last year, we raised almost $13,000 and had 650 participants," said Cook.

"We start working on it in January, and a lot of the race-committee members are county employees who worked with Tim. I run races, too, so I spend April, May and June handing out flyers at other races in which I’m running.”

Cook has been running since high school. “This is one of my passions outside of work,” he said. “We get a lot of positive feedback on the Tim Harmon 5K. I feel good when I hand a flyer to someone and get compliments from people who’ve done this race previously and really liked it. We get lots of repeat customers.”

Literature in the race packets educates people about hepatitis C and how to avoid contracting It. Harmon's disease was discovered through a routine blood test, but no cure is available. It has no symptoms, so people don't realize they have it until they're diagnosed. But by then, their livers may be irreparably damaged and that's what happened to Harmon. For more information, call 1-800-891-0707 or see www.hepfi.org.

“Over 4 million people in the U.S. have been infected with the virus, but as many as half of them do not know they’ve been infected,” said Cook. “At least 75 percent of those infected develop chronic hepatitis, and 30 percent of them go on to develop cirrhosis of the liver. Chronic liver disease due to Hepatitis C causes 20,000 deaths each year in the United States, alone."

That’s why Cook’s pleased that all the proceeds from the Tim Harmon 5K are donated to charity. “We’ve probably raised about $125,000, over 10 years, and that’s a pretty good chunk of change,” said Cook.

The American Red Cross has been fined more than $16 million by the FDA for violating federal regulations on collection and manufacturing of blood products.

The FDA announced that it was fining the American Red Cross for a number of violations of federal laws, as well as for violating a 2003 consent decree between the Red Cross and FDA that was reached after the company was previously fined for blood collection errors. However, the FDA said that despite the violations and the fines, inspectors never found any evidence that the Red Cross endangered patients or the nation’s blood supply.

The Red Cross’s fines total $16.18 million; including $9.79 million in fines for the mismanagement of blood products, and $6.39 million in fines for violating Good Manufacturing Practices. The violations came as a result of 12 FDA inspections conducted since February 2008 at Red Cross facilities across the country.

FDA inspectors found that on a number of occasions the Red Cross failed to promptly conduct adequate investigations, failed to develop and implement adequate corrective actions to resolve problems, and failed to ensure that problems did not reoccur.

Specifically, inspectors found instances of blood components or whole blood number mix-ups, and failure to properly track suspect blood or blood components. Suspect blood components are blood products which could carry the risk of a bloodborne disease or infection that could be transmitted to recipients of blood products, such as HIV or Hepatitis C. The suspect blood products were not distributed, according to inspection report letters sent by FDA to Red Cross.

The fines were assessed under a 2003 consent decree between FDA and Red Cross, reached between the agency and the non-profit organization after similar problems were discovered in 1993. The consent decree allows the FDA to impose significant fines on Red Cross when the organization fails to comply with federal blood collection regulations. Before the most recent fines, the Red Cross has been fined about $21 million by FDA since the consent decree.

Two new studies on viral pathogens in oysters and mollusks shed new light on the need for better detection methods and treatments that are needed to ensure shellfish safety.

Over the past few years both the United States and Europe have reported several foodborne illness outbreaks related to contaminated oysters and other mollusks.

The first study, by Spanish researchers, appeared in Emerging Infectious Diseases (EID). In it, scientists analyzed 50 mollusk samples imported into Spain from Sep 2006 to Mar 2009 for the presence of three human enteric viruses, including two norovirus genotypes, hepatitis A, and astrovirus. Species included clams, oysters, cockles, and razor clams. The mollusks were imported from Morocco, Peru, Vietnam, and South Korea.

According to the Center for Infectious Disease Research and Policy, real-time reverse transcription polymerase chain reaction (RT-PCR) testing was used to detect norovirus and hepatitis A and standard RT-PCR was used to detect astrovirus.

Researchers found that 40 percent of the 50 samples were contaminated by at least one virus, though they all had met current food safety standards. Present in 24 percent of samples was norovirus genotype 1, followed by astrovirus--found in 18 percent of samples, norovirus genotype 2--found in 8 percent, and hepatitis A.

Six of the positive samples tested positive for more than one virus. The authors noted that infections with multiple virus strains could produce more severe symptoms and possibly lead to the emergence of new recombinant strains.

The researchers recognized the difficulty of detecting and monitoring viral contamination in shellfish samples, however, they believe the new prevention strategies based on microbiological risk assessment could help ensure product safety and that it's essential to implement such steps and provide good lab training in developing countries that export the products.

In the second study, which appears in Eurosurveillance, Irish researchers reported on a method they tested to reduce possible oyster contamination in harvesting areas linked to gastroenteritis outbreaks. The research team noted that methods for detecting norovirus in shellfish are relatively new and that processes to eliminate bacteria in oysters--putting them in clean seawater at ambient temperatures so they can purge their contaminants--do little to reduce virus levels in oysters.

Oysters from an Irish harvesting area linked to norovirus outbreaks were used to test a modified "depuration" method involving the re-laying of oysters in clean areas for 17 days, then subjecting them to elevated water temperatures (15C to 17C) for at least 4 days.

The researchers reported that after treatment, norovirus levels in the re-laid oysters decreased from 2,900 to 492 genome copies. Exposing them to the higher temperatures for 4 days reduced norovirus levels to 136 viral genome copies. The level fell below assay detection at 6 days.

The group concluded that growing evidence suggests that it is possible to gauge illness risk based on norovirus levels in oysters and that given the inadequacy of existing controls to prevent contamination, setting an appropriate virus standard would yield public health benefits.

They also wrote that validated treatment processes can be used to produce a safe product, even when low levels of norovirus are detected in the treated oysters.

Objectives: To elucidate the efficacy of interferon (IFN)-beta induction therapy followed by pegylated IFN alpha and ribavirin for chronic infection with hepatitis C virus (HCV). Methods: Patients chronically infected with HCV genotype 1, high titer were enrolled. Twice daily bolus injections of 3 million units IFN-beta were administered for 14 days. Thereafter, weekly injection of pegylated IFN alpha 2b and daily intake of ribavirin were followed. Therapy duration was adjusted according to the response to the therapy. When time to an undetectable HCV-RNA was 1, 2, 4, 8, and 12 weeks, total duration of therapy was 12, 24, 36, 48 and 60 weeks, respectively. Patients who failed to achieve an undetectable HCV-RNA within 12 weeks discontinued therapy on 12 week. Results: Among the 101 patients treated, 56 (55.4%) achieved sustained virological response (SVR). SVR rate for each treatment duration was 10/10 for 12 weeks, 12/14 for 24 weeks, 18/19 for 36 weeks, 15/26 for 48 weeks, 1/4 for 60 weeks and 0/28 for patients who discontinued therapy at 12 weeks. Mean time to an undetectable HCV-RNA was 35.5 +/- 2.7 days. Mean therapy duration was 27.3 +/- 1.4 weeks. Using a cut off value of 21.5 fmol/L of HCV core-antigen in the first week, SVR could be predicted by sensitivity of 0.91 and specificity of 0.78. Conclusion: IFN-beta induction therapy resulted in acceptable SVR rates despite short therapy duration. Steep reduction of HCV by IFN-beta enables us to predict SVR in the first week of therapy.

Currently, hepatitis C virus (HCV) antiviral therapy is characterized by long duration, a multitude of side effects, difficult administration and suboptimal success; clearly, alternatives are needed. Collectively, specifically targeted antiviral therapy for HCV (STAT-C) molecules achieve rapid viral suppression and very high rapid virological response rates, and improve sustained virological response rates. The attrition rate of agents within this class has been high due to various toxicities. Regardless, several STAT-C molecules are poised to become the standard of care for HCV treatment in the foreseeable future. Optimism must be tempered with concerns related to the rapid development of drug resistance with resulting HCV rebound. Strategies including induction dosing with interferon and ribavirin, use of combination high-potency STAT-C molecules and an intensive emphasis on adherence to HCV antiviral therapy will be critical to the success of this promising advance in HCV therapy.
PMID: 20559582 [PubMed - in process]

ScienceDaily (Mar. 24, 2010) — Curcumin, one of the principal components of the Indian spice turmeric, seems to delay the liver damage that eventually causes cirrhosis, suggests preliminary experimental research in the journal Gut.

Curcumin, which gives turmeric its bright yellow pigment, has long been used in Indian Ayurvedic medicine to treat a wide range of gastrointestinal disorders.

Previous research has indicated that it has anti-inflammatory and antioxidant properties which may be helpful in combating disease.

The research team wanted to find out if curcumin could delay the damage caused by progressive inflammatory conditions of the liver, including primary sclerosing cholangitis and primary biliary cirrhosis.

Both of these conditions, which can be sparked by genetic faults or autoimmune disease, cause the liver's plumbing system of bile ducts to become inflamed, scarred, and blocked. This leads to extensive tissue damage and irreversible and ultimately fatal liver cirrhosis.

The research team analysed tissue and blood samples from mice with chronic liver inflammation before and after adding curcumin to their diet for a period of four and a period of eight weeks.

The results were compared with the equivalent samples from mice with the same condition, but not fed curcumin.

The findings showed that the curcumin diet significantly reduced bile duct blockage and curbed liver cell (hepatocyte) damage and scarring (fibrosis) by interfering with several chemical signalling pathways involved in the inflammatory process.

These effects were clear at both four and eight weeks. No such effects were seen in mice fed a normal diet.

The authors point out that current treatment for inflammatory liver disease involves ursodeoxycholic acid, the long term effects of which remain unclear. The other alternative is a liver transplant.

Curcumin is a natural product, they say, which seems to target several different parts of the inflammatory process, and as such, may therefore offer a very promising treatment in the future.

ScienceDaily (June 9, 2010) — How does the liver manage to regenerate itself even after severe damage? Seeking to find an answer to this significant medical question, scientists of the HepatoSys/German Virtual Liver Network have gained new insights into the underlying processes involved in the regeneration of liver lobules using computer simulation and laboratory experiments.

What that looks like has been demonstrated at the third Conference on Systems Biology of Mammalian Cells (SBMC) from June 3-5, 2010 at the Concert Hall (Konzerthaus) in Freiburg (http://www.sbmc2010.de/). The new perspectives on liver regeneration open the door to developing new treatments for cirrhosis and other injuries to this vital organ.

The singular mechanisms of liver regeneration

The liver is a very special organ: even if more than fifty percent of its overall mass is damaged -- for instance, by intoxication -- it can regenerate itself completely. This amazing ability is essential. The liver is the body's most important metabolic organ and has the task, among others, of detoxifying the blood. To enable it to do this, the liver is equipped with a very complex anatomy: in humans both hepatic lobes are composed of about a million small lobules that are a maximum of one to two millimeters in size.

The blood flowing into the liver enters the lobules via the so-called portal field, which separates neighboring lobules from each other. From there it flows through microvessels surrounded by hepatocytes -- the most common type of cell in the liver -- and drains into a centrally located vein. This special architecture ensures that the blood is brought into optimal contact with the hepatocytes when it flows through the organ.

When a liver has recovered after damage caused by drugs, alcohol consumption or a viral infection, this complex architecture must be restored. The underlying mechanisms are still poorly understood. HepatoSys researchers led by Dirk Drasdo at the Interdisciplinary Centre for Bioinformatics in Leipzig (IZBI) and the French National Institute for Research in Computer Science and Control (INRIA) in Le Chesnay near Paris have started investigating liver regeneration using computer-based methods of systems biology: Drasdo and his team simulated the scenario after intoxication with carbon tetrachloride (CCl4) in mice -- a typical animal model for paracetamol intoxication in humans -- on the computer.

From the tissue section to the computer

The first of three steps was to obtain a computer representation of an average liver lobule. Working closely with the experimental research group led by Jan Hengstler of the Leibniz Institute and the University of Dortmund, the scientists recorded parameters necessary to quantitatively characterize the static lobule architecture, such as the shape and orientation of the blood vessels, and the shape, orientation and spatial organization of the hepatocytes. These parameters were extracted using image processing methods that allow the full three-dimensional reconstruction of microscopic images of specially prepared serial tissue sections, followed by turning the three-dimensional patterns into numbers.

The second step was to record the regeneration process in the liver lobules of mice. The animals were injected with the liver-damaging substance carbon tetrachloride, which -- like paracetamol intoxication -- results in the death of hepatocytes near the central vein of the liver lobule. To characterize the regeneration process quantitatively, the scientists introduced so-called process parameters. These parameters -- also obtained from image analysis -- record when and where new hepatocytes are created and register their movements and alignment within the organ in the process of regenerating the original architecture of the liver lobule.

Finally, based on all these parameters a mathematical model was developed with which the spatial- temporal dynamics of individual hepatocytes and blood vessels could be simulated on a computer. With their computer model the scientists managed to identify previously unrecognized mechanisms during regeneration in liver lobules. As it turned out, the new cells do not just emerge at arbitrary locations within the lobule; "Instead it quickly became evident that the spatio-temporal process can only function properly if the new hepatocytes align themselves along the sinusoids, the micro-blood vessels that traverse the liver lobule," explains Drasdo's co-worker Stefan Höhme. This observation on the basis of the computer model was subsequently confirmed on real liver lobules in a laboratory experiment. "That," according to Höhme, "brings us closer to an understanding of the complex processes involved in liver regeneration."

Not only for the liver

As Drasdo emphasizes, such a dynamic model of a multi-cellular arrangement capable of making correct predictions is still a great exception: "It simultaneously records single cells and the whole tissue," he says. "And that creates the basis for examining in more detail the signalling processes within and among the cells that control regeneration."

The same principle can be applied to build models for other medically relevant questions, e.g. how a tumor spreads to other parts of the body. Understanding these dynamic processes paves the way for new and effective treatments, e.g. to support the liver during the regenerative process or to hinder tumor progression. "Our work was only possible because we were able to work hand in hand with the experimental research group led by Jan Hengstler in Dortmund," emphasized Drasdo, who has many years of experience in modeling cells and cell aggregates. "Only then could we validate the results from our computer simulations directly with an experiment and calibrate our models with experimental data- that is exactly what constitutes systems biology."

ScienceDaily (June 15, 2010) — A team led by researchers from the Center for Engineering in Medicine at Massachusetts General Hospital (MGH) has developed a technique that someday may allow growth of transplantable replacement livers. In a study appearing in Nature Medicine, the investigators describe using the structural tissue of rat livers as scaffolding for the growth of tissue regenerated from liver cells introduced through a novel reseeding process.

"Having the detailed microvasculature of the liver within a biocompatible, natural scaffold is a major advantage to growing liver tissue in a synthetic environment," says Basak Uygun, PhD, research associate at the MGH Center for Engineering in Medicine (MGH-CEM) and the paper's lead author. "Our technique of 'decellularizing' organs leaves the vascular system intact, which facilitates repopulation of the structural matrix and the subsequent survival and function of the introduced liver cells."

Liver transplantation is the only effective treatment for liver failure but is greatly limited by the shortage of donor organs. Each year 4,000 individuals who might have survived with a liver transplant die in the U.S. The shortage of donor livers and other organs is a major force behind the emerging field of tissue engineering and regenerative medicine. Efforts to build tissues from the ground up have not yet approached the goal of transplantable replacement organs, and replacing the liver -- in which each cell is a metabolic factory requiring constant, direct contact with the vascular system -- has been particularly challenging.

The current report describes a refinement of an approach to re-engineering replacement rat hearts that was reported in 2008 by University of Minnesota researchers. Since liver tissue is much more delicate than the muscular structure of the heart, the MGH-CEM team developed a gentler way of flushing living cells out of the liver's structural matrix, which is primarily made of connective tissue like collagen. After the cells were removed, the lobular structure of the liver and its extracellular matrix remained. Containing specific biochemical signals and cues that would direct liver cells to travel to the correct location and resume function -- something quite difficult to replicate using synthetic methods -- the matrix also maintained the organ's intricate network of blood vessels.

Another novel technique was used to reintroduce hepatocytes, the cells that carry out most of the liver's primary functions, into the decellularized matrix. The MGH-CEM approach actually caused cells to penetrate the vascular network and become embedded in the matrix, leaving major vessels clear to carry the essential blood supply. The repopulated matrix displayed normal liver function for up to 10 days in culture, and recellularized grafts were successfully connected to the circulation of live rats with minimal cellular damage and normal hepatocyte function.

"As far as we know, a transplantable liver graft has never been constructed in a laboratory setting before," explains Korkut Uygun, PhD, of the MGH-CEM, the paper's senior author. "Even though this is very exciting and promising, it is a proof-of-concept study only. Much more work will be required to make long-term functional liver grafts that can actually be transplanted into humans. We haven't been able to go beyond several hours in the rats, but it's a great start."

Martin Yarmush, MD, PhD, director of the MGH-CEM and a co-author of the Nature Medicine study, explains that the quarter of a million donor livers discarded each year because they are not suitable for transplantation would be an obvious source of supply for the creation of whole-organ scaffolds. "There is great potential for constructing full-fledged liver lobes containing animal or human cells, but several thorny issues must first be tackled, including formation of a layer of endothelial cells to line graft blood vessels," he says. "Given enough careful work, this approach could ultimately revolutionize tissue engineering and provide real working grafts for the liver and other complex tissues." Yarmush and Korkut Uygun both have faculty appointments at Harvard Medical School.

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